Project Summary: Convergent evidence from clinical and preclinical studies have highlighted the deleterious effects of aberrant accumulation of the amyloid beta (A?42) peptide, from neuronal dysfunction to behavioral and psychological manifestations of disease. Compelling evidence from recent clinical studies reveal that elevated levels of A?42 peptides are associated with anxiety and depression symptoms in middle-aged and older non-demented adults, as well as those with mild cognitive impairment (MCI) or in early stages of Alzheimer's disease (AD). Stress is a risk factor for psychiatric disease, as well as for developing AD. Further, it has been demonstrated that amplification of the stress system disrupts cellular and molecular processes at the synapse, promoting the production and secretion of A?42 peptides. The norepinephrine (NE)- locus coeruleus (LC) system is a stress-responsive neurocircuit implicated in stress-related psychiatric disorders, and in the etiology and progression of AD. Numerous studies in the literature support a role for NE as a regulator of A?42 peptide levels, as there are cellular mechanisms by which NE can influence both the production and the degradation and clearance of A?42 peptides. However, there exist significant gaps in knowledge regarding how NE regulates A?42 peptide levels. Early dysregulation of the NE system is thought to underlie the behavioral and psychiatric symptoms of dementia (BPSD), which are often the first symptoms observed in MCI patients that later progress to AD. Because NE can exert profound effects on the production and clearance of A?42 peptides, the dysregulation of NE under conditions of chronic stress, psychiatric disease, or LC degeneration may directly contribute to aberrant accumulation of A?42 peptides. Thus, targeting the LC-NE system may be a novel avenue to modulate A?42 levels in early stages to slow or halt the progression of disease. The proposed studies aim to investigate the role of NE in regulating amyloid beta A?42 peptide levels. We will build on our recent published work showing anatomical localization of A?42 peptides to LC somatodendritic processes and to noradrenergic axon terminals of the nave male and female rat medial prefrontal cortex (mPFC), a region important for the integration of the stress response and a major projection site of LC neurons. We also examined consequences of NE depletion on A?42 peptides using genetic deletion of D?H, the NE synthesizing enzyme. Results showed that NE depletion significantly decreased levels of A?42 peptides as measured by ELISA. Moreover, in a model that utilizes increased excitatory input to augment LC activity, simulating chronic stress, there is increased localization of A?42 to somatodendritic processes of the LC. These data have informed our current approach to examine dynamic regulation of A?42 levels following LDOPS administration in D?H knockout mice and in D?H-CRE x floxed Adra2a mice, a more direct model of increased NE transmission. Both males and females will be examined to probe for potential sex differences in mechanism of action of NE on A?42 peptide levels.